Process for preparing 8-oxabicyclo[3.2.1]-octane-1-acetic acids

ABSTRACT

The preparation of racemic 1R, 4R, 5R-5-(4&#39;, 8&#39;-dimethyl-5&#39;-hydroxy-7&#39;-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]-octane-1-acetic acid is described. The cycloheptane compounds are active uteroevacuant agents.

This is a division, of application Ser. No. 237,321, filed Feb. 23,1981, now U.S. Pat. No. 4,322,357.

The present invention relates to novel cycloheptane compounds having thefollowing formula. ##STR1## In compound IA the 4-oxygen and the 5-methylgroup are cis while in compound IB the 4-oxygen and the 5-methyl groupare trans.

The novel cycloheptane compounds are prepared as racemic mixturesaccording to the scheme outlined below. Although four diasterioisomersare formed with respect to the ring chiral centers at C₁, C₄ and C₅during the course of the reactions, for the purpose of simplificationonly the 1R, 4R, 5R (I-A) and 1S, 4S, 5R (I-B) structures are shown. Thestereochemistry of the side chain chiral centers at C₅ ' and C₆ ' isunspecified to indicate that all the possible isomers with respect tothese centers are also formed. In total, sixteen isomers are formed, astheoretically expected with respect to all the chiral centers (C₁, C₄,C₅, C₅ ' and C₆ ', the stereochemistry at C₁ being dictated by that atC₄). ##STR2##

In the above schemes, PCC is pyridinium chlorochromate; DIBAH isdiisobutylaluminum hydride; TsOH is tosic acid; THF is tetrahydrofuran;and HMPA is hexamethylphosphoramide.

The first step in the preparation of the cycloheptane compounds (IA andIB) involves the reaction of a cyclohexanone (1) with diazoethane toform the appropriate 5-oxygen-substituted-2-methylcycloheptanone 2a or2b. The reaction is carried out in a suitable solvent such as ethanol orether, and at a temperature between -10° C. and room temperature. Thehydroxy group of the 5-hydroxy compound (2b) is protected by convertingit to the t-butyldimethylsilyl ether (5) by reaction with thecorresponding silyl chloride in a suitable solvent such asdimethylformamide. The appropriately 5-protected cycloheptanone (2a or5) is then alkylated by means of a base catalyzed Michael addition withacrylonitrile to afford the corresponding2-cyanoethylated-2-methylcycloheptanone (3 or 6). The reaction iscarried out in a suitable solvent such as dimethoxyethane, for example,at a temperature between about -15° C. and room temperature. Reductionof the keto group with a suitable reducing agent, such as sodiumborohydride or potassium borohydride, for example, in a suitable solventsuch as ethyl alcohol, methanol, water, tetrahydrofuran, and the like,gives an approximately 30:70 mixture of the corresponding epimericcycloheptanols of 4 or of 7 wherein the hydroxyl group and the methylgroup are both cis (A) and wherein the hydroxyl group and the methylgroup are both trans (B). The epimeric cycloheptanols can be separatedby physical means such as, for example, chromatography on silica gelusing mixtures of ethyl acetate and hexane as the eluent or bypreparative liquid chromatography. The isolation of the stereochemicallypure epimers of cycloheptanols (4 and 7) at this stage establishes thebasis for sequentially obtaining the various intermediates and the endproduct acids (IA and IB) as a single pair of stereoisomers (IA or IB).

When either of the purified epimers (4A or 4B or 7A or 7B) is employedas the starting material for the synthesis of the8-oxabicyclo[3.2.1]octane-1-acetic acid, stereoselective synthesis ofthe corresponding isomers (IA and IB) is effected. For convenience, thesynthetic sequences are illustrated using a mixture of the 4(A&B) or7(A&B) isomers. The individual isomers for each of the intermediatecompounds in the sequence are easily determined in mixtures by virtue ofthe relatively constant NMR characteristics of the respective angularmethyl groups.

The free hydroxyl group in the cycloheptanol (4 or 7) is then protectedby converting the cycloheptanol to the acid resistantt-butyldiphenylsilyl ether derivative (8). The acid labilet-butyldimethylsilyl group is selectively removed with aqueous acid togive a cycloheptanol which upon oxidation with pyridinium chlorochromateaffords the corresponding ketone. (9) Acids which may be employedinclude organic acids such as acetic acid, propionic acid and the like.Solvents which can be employed for the oxidation reaction includemethylene chloride, chloroform and the like. The reaction can be carriedout at a temperature between 0° C. and room temperature. The ketone (9)can also be obtained by acid hydrolysis of the ketal (4). Acids whichcan be employed include organic acids such as acetic acid, propionicacid and the like. Removal of the t-butyldiphenylsilyl group from theketone (8) with an inorganic fluoride such as tetra-n-butylammoniumfluoride, or potassium fluoride, for example, in a suitable solvent suchas tetrahydrofuran affords the bicyclic hemiacetal (10) which isconverted to the methyl ether (11) by treatment withtrimethylorthoformate or methanol and a catalytic amount of an acid suchas sulfuric acid or p-toluenesulfonic acid.

The methyl ether (11) can also be prepared by first protecting thehydroxyl group of the cycloheptanol derivatives (4 or 7) as the acidresistant benzyl ether (22) by reaction of the cycloheptanol derivativewith a halide such as benzyl bromide for example, in a suitable solventsuch as tetrahydrofuran-HMPA. The acid labile t-butyldimethylsilyl groupcan be selectively removed with aqueous acid, such as aqueous aceticacid, to give a cycloheptanol which upon oxidation with an oxidizingagent such as pyridinium chlorochromate, for example, affords thecorresponding ketone (23). The ketone (23) can also be obtained by acidhydrolysis of the ketal (22). Debenzylation of the ketone (23) withboron tribromide or iodotrimethylsilane in a suitable solvent, such asmethylene chloride, results in the formation of the bicyclic hemiacetal(10) which in turn is converted to the methyl ether (11) by treatmentwith trimethylorthoformate or anhydrous methanol and a catalytic amountof an acid such as sulfuric acid or p-toluenesulfonic acid.

Alternatively, the methyl ether (11) can be prepared by hydrolysis ofthe hydroxyketal (4) with an aqueous inorganic acid such as hydrochloricor sulfuric acid or with p-toluenesulfonic acid to give the bicyclichemiacetal (10) followed by treatment of the reaction product withtrimethylorthoformate or anhydrous methanol and a catalytic amount of anacid such as sulfuric acid or p-toluenesulfonic acid. The methyl ether(11) can be prepared directly from the hydroxyketal (4) by treatmentwith methanol and a catalytic amount of an inorganic acid such assulfuric acid or hydrochloric acid, or p-toluenesulfonic acid.

Reduction of the nitrile (11) with a reducing agent such asdiisobutylaluminum hydride in a suitable solvent such as toluene givesthe corresponding aldehyde (12). The reaction is preferably carried outat a temperature between about -80° C. to 0° C. Reaction of the aldehyde(12) with the ylide of triethylphosphonopropionate in a suitable solventsuch as tetrahydrofuran (other solvents) affords the α,β-unsaturatedester (13). Catalytic hydrogenation of the ester (13) gives thesaturated ester (14). Catalysts which can be employed include palladiumon carbon, platinum oxide and the like. Suitable solvents include ethylacetate, methanol and tetrahydrofuran. The saturated ester (14) is thenconverted to the corresponding aldehyde (16) either by direct reductionwith a reducing agent such as diisobutylaluminumhydride, for example, orby first reducing it with a reducing agent such as lithium aluminumhydride to the carbinol (15) which is then oxidized with a suitableoxidizing agent such as pyridinium chlorochromate. Suitable solvents forthe reduction include tetrahydrofuran, toluene and hexane. Suitablesolvents for the oxidation include methylene chloride, chloroform andthe like.

The Grignard reaction of 3-methyl-3-butenylmagnesium bromide with thealdehyde (16) gives the secondary alcohol (17) which is protected as itsester (18) by treatment with a lower alkanoic anhydride such as aceticanhydride, propionic anhydride, butyric anhydride, valeric anhydride andthe like, an alkanoic acid halide such as acetyl chloride or propionylchloride or an aroyl acid halide such as benzoyl chloride in thepresence of a base such as pyridine. The terminal double bond in thelong side chain is isomerized to the more stable isopropylidene moiety(19) by reaction with an acid such as tosic acid or camphorsulfonicacid, for example, in a suitable solvent such as benzene, toluene, orxylene. The reaction is preferably carried out at the reflux temperatureof the solvent. Removal of the methyl acetal group with dilute inorganicacid such as hydrochloric acid, for example, gives the hemiacetal (20)which is condensed with (carbethoxyethylidene)triphenylphosphorane toafford the diester (21). The condensation reaction is preferably carriedout at a temperature between about 80° C. to 150° C. Hydrolysis of thediester with alcoholic base, such as sodium hydroxide in methanol, forexample, gives the racemic acid (IA and IB). The compounds can beseparated by gas chromatography of their di-trimethylsilyl derivatives.The cycloheptane compounds are active uteroevacuant agents. Thecompounds are effective in interrupting pregnancy at dosage levelsbetween about 20 mg/kg and 400 mg/kg. The actual dosage employed willdepend upon the species of animal to which the compound is administered.The compounds can be administered in formulations prepared according toacceptable pharmaceutical practices. Suitable formulations would includesolutions, suspensions and solid dosage forms in pharmaceuticallyacceptable carriers. The compounds can be administered orally or in anyconventional manner in accordance with acceptable pharmaceuticalpractices.

The following examples describe the invention in greater particularityand are intended to be a way of illustrating but not limiting theinvention.

EXAMPLE 1 (±) 5-Ethylenedioxy-2-methylcycloheptanone (2-a)

An ether solution of diazoethane is prepared as follows:N-ethyl-N-nitrosourea (70 g, 0.6 mol) is added in small portions to acooled (-10° C.) stirred mixture of ether (500 ml) and 50% aq. KOH (100ml) in a 1 liter Erlenmeyer flask over a period of 1 hour. The mixtureis stirred for an additional 0.3 hours at -10° C. and the yellow etherlayer containing diazoethane is decanted. The aqueous layer is stirredat -10° C. with additional ether (100 ml) for 15 minutes and thendecanted. The combined ether phase (˜540 ml) is dried for 0.5 hours withKOH pellets (˜25 g). The molarity of the diazoethane solution (0.235 M)is determined by titration of an aliquot (2×5 ml) with a known weight ofexcess benzoic acid which in turn is back titrated with 0.1 N NaOH.

To this diazoethane solution (530 ml, 0.124 mol) at -10° C. is added asolution of 4-ethylenedioxy-2-methylcyclohexanone (15.48 g, 0.099 mol)in ethanol (353 ml) over a period of ˜10 minutes. The cooling bath isremoved and the solution is stirred at room temperature for 2 hours.Excess diazoethane is decomposed by adding acetic acid. Removal of thesolvent in vacuo affords a liquid (18.4 g) containing (±)5-ethylenedioxy-2-methylcycloheptanone as the major component.

A portion of the crude product (5.8 g) is applied to a column of silicagel (300 g). The desired product (±)5-ethylenedioxy-2-methylcycloheptanone (2.1 g) is eluted with 2% ethylacetate/CH₂ Cl₂. NMR (CDCl₃)δ: 1.10 (d, J=7 Hz, 3H, 2--CH₃), 3.95 (s, 4,O--CH₂ --CH₂ O Ir (neat)μ: 5.87 (C═O), 9.14 (C--O--C); GC/ms: One majorcomponent is observed in the RGC. m/e: 184 (M⁺).

EXAMPLE 2 (±) 5-Hydroxy-2-methylcycloheptanone (2-b)

To a freshly prepared solution of diazoethane in ether (˜550 ml of 0.297M=163 mmol) cooled to -10° C. and well stirred with a magnetic stirrerin an open 1 liter Erlenmeyer flask is added slowly a solution of4-hydroxycyclohexanone (14.8 g, 13 mmol) in ethanol (150 ml) over aperiod of 15 minutes. The cooling bath is removed and the stirredreaction mixture is allowed to come to room temperature and stirredovernight. The excess diazoethane is discharged by adding a few drops of10% aq. acetic acid and then the solvent is removed in vacuo. Theresidue is dissolved in ether, washed with a satd. aq. NaHCO₃ solution,dried (Na₂ SO₄) and the ether is removed in vacuo. Distillation of theresidue in vacuo affords (±) 5-hydroxy-2-methylcycloheptanone whichexists as an equilibrium mixture with its tautomeric bicyclic hemiacetalform (bp, 1.4 mm, 97°-99°, 17.51 g, 95%). IR (neat)μ: 2.93 (OH), 5.90(C═O); NMR (CDCl₃)δ: 0.91 (d, J=7 Hz, 2-CH of 2-y), 1.08 (d, J=7 Hz,2--CH₃), 3.4-4.5 (m, H--C<--OH and H--C<--O--C); GC-MS: RGC shows twocomponents (˜60:40) both of which show M⁺ 142 and identicalfragmentations. MOX derivatization gave a single peak in RGC with M⁺171.

EXAMPLE 3 (±) 2-(2'-Cyanoethyl)-5-ethylenedioxy-2-methylcycloheptanone(3)

To a stirred solution of (±) 5-ethylenedioxy-2-methylcycloheptanone(18.0 g, 98 mmol) in dimethoxyethane (30 ml) at -10° C. is added 30%KOH/methanol (1.5 ml) followed by acrylonitrile (10.39 g, 196 mmol). Thesolution is stirred overnight at room temperature, diluted with ether(300 ml), and washed with distilled water and brine. The organic phaseis dried (Na₂ SO₄), filtered, and the solvent removed in vacuo to afforda yellow solid (23.6 g) containing (±)2-(2'-cyanoethyl)-5-ethylenedioxy-2-methyl-cycloheptanone as the majorproduct. A second similar reaction using crude5-ethylenedioxy-2-methylcycloheptanone (16.5 g) affords additional crudeproduct (22.7 g). The combined crude product (46.3 g) is applied to acolumn of silica gel (2 kg) and eluted with increasing gradients ofethyl acetate/hexane. The desired cycloheptanone is eluted with ˜30%ethyl acetate/hexane (21.3 g, 55%). Recrystallization of thecycloheptanone (4 g) from ether/hexane affords (±)2-(2'-cyanoethyl)-5-ethylenedioxy-2-methyl-cycloheptanone (2.29 g) as awhite crystalline solid, mp 58°-60°. NMR (CDCl₃)δ: 1.08 (s, 3,2--CH.sub. 3), 3.88 (s, 4, O--CH₂ --CH₂ --O--); IR (neat)μ: 4.47(C.tbd.N), 5.90 (C═O), 9.05 (C--O--C); GC/MS: One major fraction isobserved in the RGC. m/e. 237 (M⁺).

EXAMPLE 4 (±)1S,2R-2-(2'-Cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol (4-A)

Sodium borohydride (7.13 g, 10 equiv.) is added to a stirred solution of(±) 2-(2'-cyanoethyl)-5-ethylenedioxy-2-methyl-cycloheptanone (16.4 g)in methanol (400 ml) at 0° C. under nitrogen over a 15 minute period.The cooling bath is removed and the solution is stirred overnight atroom temperature. The solvent is removed in vacuo and the residue istreated with satd. NH₄ Cl solution and extracted with CH₂ Cl₂. Thecombined organic phase is washed (brine), dried (Na₂ SO₄), filtered, andevaporated in vacuo to afford a white crystalline solid mixture (13.7g). The mixture is recrystallized from ether to afford a solid (4.6 g,28%, mp 66°-68°), which is mainly the trans alcohol (˜95% by nmr) (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol. Thepure alcohol is obtained by several recrystallizations from ether, mp68°-70° C. NMR (CDCl₃)δ: 0.97 (s, 3, 2--CH₃), 3.47 (m, 1, 1-H), 3.88 (s,4, O--CH₂ CH₂ --O--), IR (neat)μ: 2.88 (OH) 4.45 (C.tbd.N); GC/MS: TheRGC consists of one major fraction. m/e: 221 (M⁺ --H₂ O).

EXAMPLE 5 (±)1R,2R-2-(2'-Cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan- 1-ol (4-B)

Following the isolation of (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol from amixture of (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol and (±)1R,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol bycolumn chromatography on silica gel with 35% ethyl acetate/cyclohexane,further elution with 35-50% ethyl acetate/cyclohexane gives the cisisomer (±)1R,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol, mp78°-79° C. IR (KBr)μ: 2.86 (OH), 4.46 (C.tbd.N); NMR (CDCl₃)δ: 0.93 (s3H, 2--CH₃), 4.33 (m, 1H, 1-H), 3.92 (s, 4H, --OCH₂ --CH₂ --O).

EXAMPLE 6 (±)2-(2'-Cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxycycloheptanone (6)

Substituting (±) 2-methyl-5-t-butyldimethylsilyloxycycloheptanone for(±) 5-ethylenedioxy-2-methylcycloheptanone in the procedure for thepreparation of (±)2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptanone, there isobtained (±)2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxycycloheptanone. IR(neat)μ: 4.42 (C.tbd.N), 5.9 (C═O); NMR (CDCl₃ -CHCl₃ as ref. at 436Hz)δ: 0.1 [S, 6H, OSi(CH₃)₂ ], 0.93 [s, 9H, OSi(CH₃)₂ --C(CH₃)₃ ], 1.13(s, 3H, 2--CH₃), 3.95 (bm, 1H, 5-H); MS: 294 (M⁺ --CH₃).

EXAMPLE 7 (±) 1S,2R and (±)1R,2R-2-(2'-Cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxycycloheptan-1-ol(7-A and 7-B)

Substituting (±)2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxycycloheptanone for(±) 2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptanone in theprocedure for the preparation of (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol amixture of isomers is obtained which can be separated by chromatographyon silica gel to give (±) 1S,2R and1R,2R-2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxycycloheptan-1-ol.

EXAMPLE 8 (±) 5-t-Butyldimethylsilyloxy-2-methylcycloheptanone (5)

Imidazole (2.45 g, 31.6 mmol) is added to a solution of (±)5-hydroxy-2-methylcycloheptanone (2.03 g, 14.3 mmol) indimethylformamide (35 ml) at 0° C. followed by t-butyldimethylsilylchloride (2.38 g, 15.7 mmol) under nitrogen. The mixture is stirred atroom temperature for 17 hours and then diluted with ether (100 ml) andwashed three times with water. After drying (Na₂ SO₄), the ether isremoved in vacuo to afford (±)5-t-butyldimethylsilyloxy-2-methylcycloheptanone (3.7 g, 100%). IR(neat)μ: 5.88 (C═O); NMR (CDCl₃)δ: 0.1 (s, 6H, Si(CH₃)0.93 [s, 9H,Si(CH₃)₂ --C(CH₃)₃ ], 1.1 (d, J=2--CH₃), 3.6-4.2 (m, 1H, 5-H).

EXAMPLE 9 (±)1S,4S,5R-5-(2'-Cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol (10-B)

To a stirred solution of (±)2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol (6.5 g, 27mmol), in acetone (50 ml) is added conc. HCl (0.25 ml) under nitrogen.The solution is refluxed for 1 hour and stirred at room temperature for4 hours. The acetone is removed in vacuo. The residue is dissolved inethyl acetate (300 ml), washed (NaHCO₃, brine), dried (Na₂ SO₄), and thesolvent removed in vacuo to afford crude product (5.3 g, ˜100%). Aportion of this (1.0 g) is recrystallized (ether) to give 0.31 g ofrecrystallized product (31%), mp 102°-103°. A second recrystallization(ether) gives analytically pure (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol (0.18g, mp 104°-105°). NMR (CDCl₃)δ: 0.82 (s, 3H, 5--CH₃), 3.83 (m, 1H, 4-H);IR (KBr)μ: 2.87 (OH), 4.44 (C.tbd.N); GC/MS: One major component, m/e:195 (M⁺).

EXAMPLE 10 (±)1R,4R,5R-5-(2'-Cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol (10-A)

Substituting (±)1R,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol for (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol in theprocedure for the preparation of (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol thereis obtained (±)1R,4R,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol. IR(KBr)μ: 2.86 (OH), 4.45 (C.tbd.N); NMR (CDCl₃)δ: 1.12 (S, 3H, 5--CH₃),3.85 (m, 1H, 4-H); m/e: 195 (M⁺).

EXAMPLE 11 (±)1S,4S,5R-5-(2'-Cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methylether (11-B)

Methanolic sulfuric acid (0.4 ml of 0.2 N sulfuric acid in methanol) isadded to a solution of (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]-octan-1-ol (85mg, 4.36 mmol) in methyl orthoformate (0.7 ml, large excess) and themixture is stirred at room temperature under nitrogen for 17 hours. Thereaction mixture is treated with excess 10% aq. NaHCO₃ solution and thentaken to dryness on a rotary evaporator. The residue is partitionedbetween water and methylene chloride and the separated organic layer iswashed with brine, dried (K₂ CO₃) and evaporated to dryness to afford(±) 1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]-octan-1-olmethyl ether (79 mg). IR (neat)μ: 4.46 (C.tbd.N); NMR (CDCl₃)δ: 0.82 (s,3H, 5--CH₃), 3.38 (s, 3H, OCH₃), 3.85 (m, 1H, 4-H); 209 (M⁺).

EXAMPLE 12 (±)1R,4R,5R-5-(2'-Cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methylether (11-A)

Substituting (±)1R,4R,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol for(±) 1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol inthe procedure for the preparation of (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methylether there is obtained (±)1R,4R,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methylether. IR (neat)μ: 4.45 (C.tbd.N); NMR (CDCl₃)δ: 1.12 (s, 3H, 5--CH₃),3.40 (s, 3H, --OCH₃), 3.87 (m, 1H, 4-H); m/e: 209 (M⁺).

EXAMPLE 13 (±)1S,2R-2-(2'-Cyanoethyl)-5-ethylenedioxy-2-methyl-1-t-butyldiphenylsilyloxycycloheptane(8-B)

By substituting (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol for (±)5-hydroxy-2-methylcycloheptanone and t-butyldiphenylsilyl chloride fort-butyldimethylsilyl chloride in the procedure for the preparation of5-t-butyldimethylsilyloxy-2-methylcycloheptanone, (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methyl-1-t-butyldiphenylsilyloxycycloheptanoneis obtained after purification of the crude product by chromatography onsilica gel (8-16% ethyl acetate/cyclohexane). IR (KBr)μ: 4.46 (C.tbd.N);NMR (CDCl₃)δ: 0.98 (s, 3H, 2--CH₃), 11.06 [s, 9H, Si--C--(CH₃)₃ ], 3.38(bm, 1H, 1-H), 3.73 (s, 4H, --O--(CH₂)₂ --O--), 7.2-7.8 (m, 10H, ArH);m/e: 420 (M⁺ -57).

EXAMPLE 14 (±) 1S,2R and1R,2R-2-(2'-Cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxy-1-t-butyldiphenylsilyloxycycloheptane[8-(A+B)]

By substituting (±) 1S,2R and (±)1R,2R-2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxycycloheptan-1-olfor (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol in theprocedure for the preparation of (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methyl-1-t-butyl-diphenylsilyloxycycloheptane,there is obtained (±) 1S,2R and (±)1R,2R-2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxy-1-t-butyldiphenylsilyloxycycloheptane.

EXAMPLE 15 (±) 4R,5R and (±)4S,5R-5-(2'-cyanoethyl)-5-methyl-4-t-butyldiphenylsilyloxycycloheptan-1-one[9-(A+B)]

The ketal (±) 1S,2R and (±)1R,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methyl-5-t-butyldiphenylsilyloxycycloheptane(0.489 g) in tetrahydrofuran (5 ml) is treated with 80% aq. acetic acid(5 ml) at room temperature for 12 hours. Evaporating the mixture todryness in vacuo gives the ketone (±) 4R,5R and (±)4S,5R-5-(2'-cyanoethyl)-5-methyl-4-t-butyldiphenylsilyloxy-cycloheptan-1-one.

Alternatively, similar treatment of (±) 1S,4R and (±)1R,2R-2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxy-1-t-butyldiphenylsilyloxycycloheptanewith aq. acetic acid followed by oxidation of the crude inermediatecycloheptanol with pyridinium chlorochromate in CH₂ Cl₂ according to theprocedure described for the preparation of (±) 1R,4R,5R(cis) and (±)1S,4S,5R-(trans)-5-(5'-oxo-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]-octan-1-olmethyl ether from (±) 1R,4R,5R(cis) and (±)1S,4S,5R(trans)-5-(5'-hydroxy-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether gives (±) 4R,5R and (±)4S,5R-5-(2'-cyanoethyl)-5-methyl-4-t-butyldiphenylsilyloxycycloheptan-1-one.

EXAMPLE 16 (±) 1R,4R,5R and (±) 1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol [11-(A+B)]

A solution of (±) 4R,5R and (±)4S,5R-5-(2'-cyanoethyl)-5-methyl-4-t-butyldiphenylsilyloxycycloheptan-1-one(0.443 g) in tetrahydrofuran (5 ml) is treated with a 1 M solution oftetra-n-butylammonium fluoride (2 mmol) in tetrahydrofuran for 5 hoursat room temperature. Dilution with H₂ O and extraction with CH₂ Cl₂followed by the removal of the solvent in vacuo gives (±) 1R,4R,5R and(±) 1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol.

EXAMPLE 17 (±)1S,2R,1-Benzyloxy-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptane(23-B)

To a suspension of sodium hydride (2.24 g, 50% oil dispersion, 46 mmol,washed with hexane, 3×10 ml) in tetrahydrofuran (10 ml) and HMPA (8.1ml, 46 mmol) is added a solution of (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-methyl-8-oxabicyclo[3.2.1]octan-1-ol(5.57 g, 23 mmol) in tetrahydrofuran (50 ml) at room temperature undernitrogen with cooling. After stirring for 17 hours (n-C₄ H₉)₄ NI (3.44g, 9.3 mmol) and benzylbromide (3.3 ml, 28 mmol) are added. The mixtureis stirred for 4 hours, diluted with ether (100 ml), washed with H₂ O(150 ml) and the aqueous phase extracted with ether (3×100 ml). Thecombined ether extracts are washed (brine), dried (Na₂ SO₄), filtered,and concentrated in vacuo to afford a crude product (9.0 g) which isapplied to a column of silica gel (200 g, Baker). The purified benzylether (±)1S,2R,1-benzyloxy-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptane(4.4 g, 57%) is eluted with 15% ethyl acetate/hexane plus 0.1% pyridine(250 ml frac.). NMR (CDCl₃)δ: 0.97 (s, 3H, 2--CH₃), 3.13 (m, 1H, 1-H),3.88 (s, 4H, O--CH₂ CH₂ --O), 4.43 (ABq, J=12 Hz, 2H, O--CH₂ --φ), 7.35(s, 5H, Ar-H); IR (neat)μ: 4.50 (C.tbd.N), 9.22 (C--O--C); GC/MS: TheRGC consists of one major fraction whose spectrum corresponds to thebenzyl ketal. m/e: 329 (M⁺).

EXAMPLE 18 (±)1R,2R,1-Benzyloxy-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptane(22-A)

To a suspension of sodium hydride (1.15 g, 50% oil dispersion, 24 mmol,washed with hexane and tetrahydrofuran, 1×10 ml each) in tetrahydrofuran(2 ml) under nitrogen at 5° C., is added a solution of (±)1R,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol (2.9 g,12 mmol) in tetrahydrofuran (20 ml) followed by HMPA (4.2 ml, 24 mmol).The mixture is stirred for 2 hours at room temperature and then (n-C₄H₉)₄ NI (0.89 g, 20 mmol) and benzyl bromide (1.71 ml, 14 mmol) areadded. The mixture is stirred at room temperature for 17 hours, dilutedwith ether (200 ml), washed with H₂ O (150 ml) and the aqueous phaseextracted with ether (3×100 ml). The combined ether extracts are washed(brine), dried (Na₂ SO₄), filtered and concentrated in vacuo to affordthe crude product (8.0 g) which is purified by column chromatography(silica gel, 200 g, 15% ethyl acetate/hexane) to afford (±)1R,2R,1-benzyloxy-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptane(3.053 g, 77%) as a colorless oil. NMR (CDCl₃)δ: 0.95 (s, 3H, 2--CH₃),3.08 (m, 1H, 1-H), 3.88 (s, 4H, OCH₂ CH₂ O), 4.47 (ABq, J=12 Hz, 2H,φ--CH₂ --O), 7.32 (s, 5H, Ar-H); IR (neat)μ: 4.45 (C.tbd.N), 9.22 (COC);GC/MS: The RGC consists of one major fraction having an MH⁺ 330 usingmethane as the reagent gas (CI).

EXAMPLE 19 (±) 4S,5R and (±)4R,5R-5-(2'-Cyanoethyl)-5-methyl-4-benzyloxycyclohept-1-one [23-(A+B)]

By substituting (±) 1R,2R and (±)1S,2R-1-benzyloxy-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptanefor (±) 1S,2R and (±)1R,2R-2-(2'-cyanoethyl)-5-ethylene-dioxy-2-methyl-5-t-butyldiphenylsilyloxycycloheptanein the procedure for the preparation of (±) 4R,5R and (±)4S,5R-5-(2'cyanoethyl)-5-methyl-4-t-butyldiphenylsilyloxycycloheptan-1-one,there is obtained (±) 4S,5R and (±)4R,5R-5-(2'-cyanoethyl)-5-methyl-4-benzyloxy cyclohept-1-one. Similarlyby substituting (±) 1R,2R and (±)1S,2R-1-benzyloxy-2-(2'-cyanoethyl)-5-t-butyldimethylsilyloxy-2-methylcycloheptanefor (±) 1S,2R and (±)1R,2R-2-(2'-cyanoethyl)-2-methyl-5-t-butyldimethylsilyloxy-1-t-butyldiphenylsilyoxycycloheptanein the alternative procedure for the preparation of (±) 4R,5R and (±)4S,5R-(2'-cyanoethyl)-5-methyl-4-t-butyldiphenylsilyloxycycloheptan-1-one, thereis obtained (±) 4S,5R and (±)4R,5R-5-(2'-cyanoethyl)-5-methyl-4-benzyloxycyclohept-1-one.

EXAMPLE 20 (±) 1R,4R,5R and (±)1R,4R,5S-5-(2'-Cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol[10-(A+B)]

A solution of (±) 4S,5R and (±)4R,5R-5-(2'-cyanoethyl)-5-methyl-4-benzyloxycyclohept-1-one (0.284 g) inmethylene chloride (2 ml) at 0° C. is treated with boron tribromide(0.752 g) for 2 hours. Dilution with water and extraction with CH₂ Cl₂gives, after the removal of the solvent, (±) 1R,4R,5R and (±)1R,4R,5S-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol.

EXAMPLE 21 (±) 1R,4R,5R and (±)1S,4S,5R-5-(2'-Cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methylether [11-(A+B)]

A 30:70 mixture of alcohols (±)1S,2R-2-(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol and (±)1R,2R-2(2'-cyanoethyl)-5-ethylenedioxy-2-methylcycloheptan-1-ol (16.2 g,68 mmol) is dissolved in 0.3% H₂ SO₄ /methanol (300 ml) and stirred for4 hours at room temperature under nitrogen. The solution is poured intocold 10% NaHCO₃ (100 ml) and the methanol removed in vacuo. The aqueousphase is extracted with CH₂ Cl₂ (6×100 ml). The combined CH₂ Cl₂extracts are washed (brine), dried (Na₂ SO₄), filtered and concentratedin vacuo to afford (±) 1R,4R,5R and (±)1S,4S,5R-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methylether as a colorless oil (12.6 g, 89%). NMR (CDCl₃)δ: 0.83, 1.10 (s,each, 3H, 5--CH₃, 70:30 trans:cis, resp.), 3.37 (3, 3H, O--CH₃), 3.82(m, 1H, 4-H); IR (neat)μ: 4.46 (C.tbd.N); GC/MS: One major component m/e209 (M⁺).

EXAMPLE 22 (±) 1R,4R,5R and (±)1S,4S,5R-5-Methyl-5-(3'-oxopropyl)-8-oxabicyclo[3.2.1]octan-1-ol methylether [12-(A+B)]

Diisobutylaluminum hydride (1.4 M/toluene, 53 ml, 76 mmol) is added to(±) 1R,4R,5R and (±)1S,4S,5S-5-(2'-cyanoethyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1ol methylether (12.2 g, 59 mmol) in toluene (250 ml) under nitrogen at -80° C.over a 15 minute period. The solution is stirred at room temperature for2 hours and then refluxed with H₂ O (150 ml) for 1 hour. The mixture isextracted with CHCl₃ (5×200 ml), washed (brine), dried (Na₂ SO₄),filtered in vacuo, and concentrated to afford the crude product as ayellow oil (14 g, crude >100%) which is purified by columnchromatography (silica gel, 300 g). Elution with 15% ethylacetate/hexane affords (±) 1R,4R,5R and (±) 1S,4S,5R-5-methyl-5-(3'-oxopropyl)-8-oxabicyclo[3.2.1]octan-1-ol-methyl ether as a colorlessoil (7.0 g, 56%). NMR (CDCl₃)δ: 0.75, 1.05 (s, each, 3H each, 5--CH₃),3.35 (s, 3H, OCH₃), 3.82 (m, 3H, 4-H), 11.0 (d, J=2 Hz, 1H, CHO); IR(neat)μ: 3.68 (CHO), 5.80 (C═O); GC/MS: One major component, m/e 212(M⁺).

EXAMPLE 23 (±) 1R,4R,5R and (±)1S,4S,5R-5-(4'-Ethoxycarbonyl-3'-pentenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [13-(A+B)]

Triethyl-α-phosphonopropionate (11.78 g, 50 mmol) is added to sodiumhydride (1.78 g, 74 mmol, 2.25 eq., 50% oil dissersion, washed withhexane, 2×20 ml) in tetrahydrofuran (5 ml) at 0° C. under nitrogen. Themixture is stirred for 1 hour at room temperature and aldehyde (±)1R,4R,5R and (±)1S,4S,5R-5-methyl-5-(3'-oxopropyl)8-oxabicyclo[3.2.1]octan-1-ol methylether (7.0 g, 33 mmol) is added with cooling (ice-bath). The mixture isstirred for 1 hour at room temperature, refluxed for 1 hour, treatedwith H₂ O (40 ml), and extracted with ether (3×100 ml). The combinedether extracts are washed (brine), dried (Na₂ SO₄), filtered andconcentrated in vacuo to afford (±) 1R,4R,5R and (±)1S,4S,5R-5-(4'-ethoxycarbonyl-1-3'-pentenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether as a light yellow oil (10 g crude ˜100%), which is used inthe next step without further purification. NMR (CDCl₃)δ: 0.82, 1.12 (s,each, 3H each, 5-CH₃), 1.30 (t, J=7 Hz, 3H, CH₃ -CH₂), 1.85 (s, 3H,4'-CH₃), 3.38 (s, 3H, OCH₃), 3.82 (m, 1H, 4-H), 4.17 (q, J=7 Hz, 2H, CH₂CH₃), 6.70 (m, 1H, 3' -H, trans); IR (neat).sub.μ : 5.85 (C═O), 6.10(C═C); GC/MS: One major component, m/e 296 (M⁺).

EXAMPLE 24 (±) 1R,4R,5R and (±)1S,4S,5R-5-(4'-Ethoxycarbonylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [14-(A+B)]

The ester (±) 1R,4R,5R and (±)1S,4S,5R-5-(4'-ethoxycarbonyl-3'-pentenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (10 g crude, 33 mmol) in ethyl acetate (200 ml) ishydrogenated (1 atm) over 5% Pd/C (6 eq.) for 3 hours. The mixture isfiltered through celite and concentrated in vacuo to afford the crudeproduct which is purified by column chromatography (silica gel, 150 g,5-10% ethyl acetate/hexane) to afford purified (±) 1R,4R,5R and (±)1S,4S,5R-5-(4'-ethoxycarbonylpentyl-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether 8.4 g, 85%). NMR (CDCl₃)δ: 0.73, 1.05 (s, each, 3H each,5-CH₃), 1.23 (t, J=7 Hz, 3H, CH₃ CH₂), 3.35 (s, 3 H, OCH₃), 3.82 (m, 1H,4-H), 4.10 (q, J=7 Hz, 2H, CH₃ CH₂ O); IR (neat).sub.μ : 5.76 (C═O).

EXAMPLE 25 (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-hydroxy-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [15-(A+B)]

1R,4R,5R and1S,4S,5R-5-(4'-Ethoxycarbonyl-4'-pentyl-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (7.3 g, 24 mmol) in tetrahydrofuran (100 ml) is added tolithium aluminum hydride (0.93 g, 24 mmol) in tetrahydrofuran (100 ml)under nitrogen over a 15 minute period. The mixture is refluxed for 1hour, cooled, and then H₂ O (0.9 ml), 2 N NaOH (0.9 ml), and H₂ O (2.7ml) are added successively with cooling. The solution is extracted withethyl acetate (3×150 ml) and the combined ethyl acetate extracts arewashed (satd. NH₄ Cl soln., brine), dried (Na₂ SO₄), filtered in vacuoand concentrated to afford crude (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-hydroxy-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (6.4 g, ˜100%). NMR (CDCl₃)δ: 0.77, 1.07 (s, each, 3H each,5-CH₃), 0.92 (d, J=7 Hz, 3H, 4'-CH₃), 3.38 (s, 3H, OCH₃), 3.42 (d, J=7Hz, 2H, 5'-H), 3.87 (m, 1H, 4-H); IR (neat).sub.μ : 2.90 (OH); GC/MS:One major component, m/e: 256 (M⁺).

EXAMPLE 26 (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-oxo-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [16-(A+B)]

The alcohol (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-hydroxy-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (3.8 g, 15 mmol) in CH₂ Cl₂ (100 ml) is added to pyridiniumchlorochromate (4.8 g, 22 mmol) and sodium acetate (0.36 g, 4 mM) in CH₂Cl₂ (300 ml) over a 5 minute period at 0° C. The orange mixture turnsblack upon addition of the alcohol. The mixture is stirred for 1.5 hoursat room temperature and filtered through celite. The filtrate isconcentrated in vacuo to afford a crude product (3.8 g, 100%) which ispassed through a column of silica gel (100 g, 20% ethyl acetate/hexane)to afford the semipurified aldehyde (2.5 g, 66%). This is furtherpurified on a Waters Prep 500 HPLC (8% ethyl acetate/hexane) followed bywashing with satd. NaHCO₃ to afford pure (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-oxo-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (2.0 g, 53%). NMR (CDCl₃)δ: 0.75, 1.07 (s, each, 3H each,5-CH₃), 1.08 (d, J=7 Hz, 3H, 4'-CH₃), 3.37 (s, 3H, O-CH₃), 3.83 (m, 1H,4-H), 9.93 (d, J=2 Hz, 1H, 5'-H); IR (neat).sub.μ : 3.70 (CHO), 5.78(C═O); GC/MS: One major fraction, m/e (CI, CH₄): 255 (MH⁺).

EXAMPLE 27 (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-Hydroxy-4',8'-dimethyl-8'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [17-(A+B)]

4-Bromo-3-methyl-1-butene (2.0 g, 13 mmol) in tetrahydrofuran (4 ml) isadded to magnesium turnings (0.36 g, 15 mmol) under nitrogen over a 10minute period. The mixture is heated to 50° C. for 50 minutes. Thealdehyde (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-oxo-4'-methylpentyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (1.9 g, 7.5 mmol) in tetrahydrofuran (˜15 ml) is added at-10° C. over a 10 minute period. The solution is stirred for ˜18 hoursat room temperature, treated with H₂ O (5 ml), and extracted with ether(5×150 ml). The combined ether extracts are washed (brine), dried (Na₂SO₄), filtered, and concentrated in vacuo to afford the alcohol (±)1R,4R,5R and (±) 1S,4S,5R-5-(5'-hydroxy-4',8'-dimethyl-8'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (2.4 g crude, ˜100%). NMR (CDCl₃)δ: 0.75, 1.07 (s, each, 3Heach, 5-CH₃), 0.88 (d, J=7 Hz, 3H, 3H, 4'-CH₃), 3.38 (s, 3H, O-CH₃),3.42 (m, 1H, 5'-H), 3.87 (m, 1H, 4-H), 4.70 (m, 2H, 9'-H); IR(neat).sub.μ : 2.88 (OH), 6.08 (C═C); GC/MS: One major component, m/e:396 (M⁺, TMS).

EXAMPLE 28 (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-Acetoxy-4',8'-dimethyl-8'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [18-(A+B)]

The alcohol (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-hydroxy-4'-8'-dimethyl-8'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (2.4 g, 7 mmol), pyridine (30 ml), and acetic anhydride (10ml) are stirred at room temperature under nitrogen for 18 hours. Thesolution is treated with H₂ O (20 ml), stirred for 30 minutes, andextracted with CH₂ Cl₂ (3×100 ml). The combined CH₂ Cl₂ extracts arewashed (brine), dried (Na₂ SO₄), filtered, and concentrated in vacuo toafford a crude product (2.8 g, ˜100%) which is purified on a WatersPrep. 500 HPLC (5-10% ethyl acetate/hexane) to afford purified (±)1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-8'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol methyl ether (1.9 g). NMR (CDCl₃)δ: 0.73,1.05 (s each, 3H each, 5-CH₃), 0.87 (d, J=7 Hz, 3H, 4'-CH₃), 2.02 (s,3H, OCOCH₃), 3.35 (s, 3H, OCH₃), 3.82 (m, 1H, 4-H), 4.62 (m, 2H, 9'-H),4.70 (m, 1H, 5'-H); IR (neat).sub.μ : 5.76 (C═O), 6.06 (C═C); GC/MS: Onemajor component, m/e: 366 (M⁺).

EXAMPLE 29 (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-Acetoxy-4',8'-dimethyl-7'-nonenyl-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether [19-(A+B)]

The alkene (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-8'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (1.9 g, 5 mmol), p-toluenesulfonic acid acid (300 mg), andbenzene (100 ml) are refluxed for ˜18 hours under nitrogen. The solutionis diluted with CH₂ Cl₂ (100 ml), washed (satd. NaHCO₃, brine), dried(Na₂ SO₄), filtered, and concentrated in vacuo to afford a crude product(2.0 g, 100%) which is purified on a Waters Prep. 500 HPLC (10-20% ethylacetate/hexane) to afford pure (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-7'-nonenyl-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (1.5 g), 80%). NMR (CDCl₃)δ: 0.73, 1.05 (s each, 3H each,5-CH₃), 0.88 (d, J=7 Hz, 3H, 3H, 4'-CH₃), 1.60, 1.68 [s each, 3H each,8'-(CH₃)₂ ], 2.00 (s, 3H, OCOCH₃), 3.37 (s, 3H, O-CH₃), 3.82 (m, 1H,4-H), 4.85 (m, 1H, 5'-H), 5.02 (m, 1H, 7'-H); IR (neat).sub.μ : 5.68(C═O), 6.10 (C═C); GC/MS: One major component, m/e: 306 [M⁺ -HOAc].

EXAMPLE 30 (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-Acetoxy-4',8'-dimethyl-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol[20-(A+B)]

The methyl ether (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethy-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-olmethyl ether (1.1 g, 3 mmol) in 2 N HCl (1 ml) and acetone (50 ml) arerefluxed for 3 hours. The acetone is removed in vacuo and the residue isextracted with ethyl acetate (3×150 ml). The combined ethyl acetateextracts are washed (satd. NaHCO₃, brine), dried (Na₂ SO₄), filtered andconcentrated, in vacuo to afford (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol(0.9 g, 82%). NMR (CDCl₃)δ: 0.75, 1.08 (s each, 3H each, 5-CH₃), 0.92(d, J=7 Hz, 4'-CH₃), 1.67, 1.73 [s each, 3H each, 8'-CH₃)₂ ], 2.05 (s,3H, OCOCH₃), 3.85 (m, 1H, 4-H), 4.80 (m, 1H, 5'-H), 5.03 (m, 1H, 7'-H);IR (neat).sub.μ : 2.94 (OH), 5.78 (C═O), 6.06 (C═C); GC/MS: 425 (M⁺,TMS).

EXAMPLE 31 Ethyl [(±)1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-yl]acetate[21-(A+B)]

The hemiacetal (±) 1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-ol(0.85 g, 2.4 mmol) and (carbethoxymethylene)triphenylphosphorane (1.68g, 4.8 mmol) are heated neat at 150° C. under nitrogen for 48 hours. Thedark brown, oily product is purified by column chromatography (silicagel, 75 g). Elution with 30% ethyl acetate/hexane affords ethyl[(±)1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-yl]acetate(0.76 g, 75%). NMR (CDCl₃)δ: 0.75, 1.05 (s each, 3H each, 5-CH₃), 0.9(d, J=7 Hz, 3 4'-CH₃), 1.27 (t, J=7 Hz, 3H, CH₂ CH₃), 1.63, 1.70 [seach, 3H each, 8' (CH₃)₂ ], 2.02 (s, 3H, O-COCH₃), 2.63 (s, 2H, CH₂-COOEt), 3.82 (m, 1H, 4-H), 4.15 (q, J=7 Hz, 2H, CH₂ -CH₃), 4.80 (m, 1H,5'H), 5.07 (m, 1H, 7'-H); IR (neat).sub.μ : 5.75 (C═O); 6.06 (C═C);GC/MS: One major compound, m/e: 422.

EXAMPLE 32 (±) 1R,4R,5R and (±)1S,4S,5R-5-(4',8'-Dimethyl-5'-hydroxy-7'-nonenyl)-8-oxabicyclo[3.2.1]octane-1-aceticacid [I-(A+B)]

The ester, ethyl[(±)1R,4R,5R and (±)1S,4S,5R-5-(5'-acetoxy-4',8'-dimethyl-7'-nonenyl)-5-methyl-8-oxabicyclo[3.2.1]octan-1-yl]acetate(0.86 g), 2 N NaOH (5 ml), and methanol (5 ml) are refluxed for 1 hourunder nitrogen. The methanol is removed in vacuo and the residue isdiluted with H₂ O (distilled, 50 ml). The aqueous phase is extractedwith CH₂ Cl₂ (2×50 ml). The aqueous alkaline phase is acidified to pH 3(2 N HCl) and extracted with CH₂ Cl₂ (3×100 ml.) The combined CH₂ Cl₂extracts are washed (brine), dried (Na₂ SO₄), filtered, and concentratedin vacuo to afford the crude product (0.46 g, 65%). The acidic aqueousphase is re-extracted with ethyl acetate (3×100 ml) and the combinedethyl acetate extracts are washed, dried, filtered, and concentrated toafford additional crude product (0.34 g) which is purified by prep platechromatography (7% i-propanol/CHCl₃) to afford the crude product (0.24g, 33%). The combined samples of product (0.70 g) are dissolved in CH₂Cl₂ and filtered in vacuo to afford (±) 1R,4R,5R and (±)1S,4S,5R-5-(4',8'-dimethyl-5'-hydroxy-7'-nonenyl)-8-oxabi-cyclo[3.2.1]octane-1-aceticacid as a light yellow oil 0.56 g, 78%). NMR (CDCl₃)δ: 0.78, 1.08 (seach, 3H each, 5-CH₃, 70:30 trans: cis resp.), 0.92 (d, J=7 Hz, 3H,4'-CH₃), 1.67, 1.77 [s each, 3H each, 8'-(CH₃)₂ ], 2.70 (s, 2H, CH₂COOH), 3.48 (m, 1H, 5'-H), 3.98 (m, 1H, 4-H), 5.05 (m, 1H, 7'-H); IR(neat).sub.μ : 2.8-4.2 (COOH), 5.83 (C═O), 6.06 (C═C); GC/MS: The di-TMSderivatives of the cis and trans isomers are separated on GC (5'×2 mmID, OV-17 on 100/120 Gas Chrom Q, 170° to 230° C. at 20° C./minute) andeach show 496 (M⁺).

What is claimed is:
 1. The process for the preparation of a compound ofthe formula ##STR3## which comprises reacting a compound of the formula##STR4## with diazoethane to form a cycloheptanone of the formula##STR5## reacting the cycloheptanone with acrylonitrile to form acompound of the formula ##STR6## reacting the substituted cycloheptanonewith a reducing agent to form a cycloheptanol of the formula ##STR7##reacting the cycloheptanol with t-butyldiphenylsilyl chloride to form acompound of the formula ##STR8## reacting the reaction product with anorganic acid to form a ketone of the formula ##STR9## reacting theketone with tetra-n-butylammonium fluoride to form a bicyclic hemiacetalof the formula ##STR10## reacting the hemiacetal withtrimethylorthoformate in the presence of a mineral acid to form anacetal of the formula ##STR11## reacting the nitrile withdiisobutylaluminum hydride to form an aldehyde of the formula ##STR12##reacting the aldehyde with a compound of the formula ##STR13## to forman unsaturated ester of the formula ##STR14## hydrogenating theunsaturated ester to form a saturated ester of the formula ##STR15##reducing the ester with diisobutylaluminum hydride to form an aldehydeof the formula ##STR16## reacting the aldehyde with a Grignard reagentof the formula ##STR17## to form a secondary alcohol of the formula##STR18## esterifying the alcohol with an esterifying agent to form anester of the formula ##STR19## treating the ester with an acid selectedfrom tosic acid and camphorsulfonic acid to form an ester of the formula##STR20## reacting the reaction product with acid to form a hemiacetalof the formula ##STR21## reacting the hemiacetal with a compound of theformula

    (C.sub.6 H.sub.5).sub.3 P═CHCOOC.sub.2 H.sub.5

to form a diester of the formula ##STR22## and hydrolyzing the esterwith base, wherein R₁ is a t-butyldiphenylsilyoxy group and R₂ isbenzoyl or a lower alkanoyl group having 2-5 carbon atoms.
 2. Theprocess of claim 1 wherein the reducing agent is sodium borohydride. 3.The process of claim 1 wherein the organic acid is acetic acid.
 4. Theprocess of claim 1 wherein the mineral acid is sulfuric acid.
 5. Theprocess of claim 1 wherein the esterifying agent is acetic anhydride. 6.The process of claim 1 wherein the acid is hydrochloric acid.
 7. Theprocess of claim 1 wherein the base is sodium hydroxide.